Interrelationships Between Plasma Levels of Brain Natriuretic Peptide and Prolonged Symptoms Due to Long COVID, 2025, Masuda et al

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Interrelationships Between Plasma Levels of Brain Natriuretic Peptide and Prolonged Symptoms Due to Long COVID

Yohei Masuda, Yuki Otsuka, Kazuki Tokumasu, Hiroyuki Honda, Yasue Sakurada, Yui Matsuda, Yasuhiro Nakano, Ryosuke Takase, Daisuke Omura, Toru Hasegawa, Keigo Ueda, Fumio Otsuka

Objectives
Evidence for the usefulness of biomarkers that aid in diagnosis, assessment of severity, and prediction of prognosis in patients with long COVID is limited. The aim of this study was to clarify the characteristics of brain natriuretic peptide (BNP) in long COVID.

Methods
We conducted a retrospective observational study of patients who visited the COVID-19 aftercare outpatient clinic at Okayama University Hospital from February 2021 to April 2024.

Results
A total of 428 patients were enrolled in this study, and the patients were divided into a group with normal BNP (n = 314, ≤18.4 pg/mL) and a group with increased BNP (n = 114, >18.4 pg/mL). The long COVID group with increased BNP had a higher proportion of females (44.3% vs. 73.7%, p < 0.01) and an older median age (38 vs. 51 years, p < 0.01). Fatigue and brain fog were commonly manifested in both groups, while dyspnea was a more frequent complaint in the group with increased BNP. Various symptoms including fatigue, palpitations, and taste and/or olfactory disorders were associated with elevated BNP (23 to 24 pg/mL). Memory impairment was also linked to higher BNP (OR: 2.36, p = 0.05). In long COVID patients, plasma BNP elevation appears to be more pronounced in females and is often related to cardiogenic factors, in which inflammatory responses are also involved.

Conclusions
Plasma BNP measurement may be useful for evaluating the severity of long COVID, especially in female patients and those with respiratory symptoms and/or memory impairment.

Link | PDF (Journal of Clinical Medicine) [Open Access]

 

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We defined long COVID as “persistence of several symptoms for more than one month after the onset of COVID-19”

In the present study, the plasma BNP concentrations tended to increase with age, particularly in females. Since BNP levels have been shown to be generally elevated in males in a Japanese cohort [26], there might be some other reasons why the plasma BNP levels were elevated especially in elderly female patients in the present study.

 

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Herein, we propose two independent etiologies for the elevation of plasma BNP levels in long COVID patients. The first is a cardiogenic etiology, which is widely known. COVID-19 causes cardiac impairments in both the acute and long COVID phases including […]. Given the recent evidence suggesting that the levels of plasma BNP do not always represent cardiac abnormalities at one year after SARS-CoV-2 infection, BNP alone should not be used to assess cardiac outcomes in long COVID

Another etiology for the elevation of BNP is the existence of inflammation. Elevated levels of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α, have been observed in patients with long COVID. Additionally, there is a positive association between the levels of these cytokines and plasma BNP even in the absence of cardiovascular diseases. In the context of long COVID, BNP might not be useful as a cardiac-specific biomarker but instead might be useful as a biomarker for predicting inflammation-induced symptoms.

Considering that BNP is also produced by ischemic skeletal muscle satellite cells, functioning as a paracrine regulator of vasodilation and/or vascular regeneration [21], some extra-cardiovascular factors might also be involved in the changes in plasma BNP levels in long COVID patients.

[21] is A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity (2022, Nature Communications) which says —

BNP is produced in ischemic skeletal muscle satellite cells as a potential paracrine regulator of vasodilatation and vascular regeneration. [40]

[40] is The natriuretic peptide/guanylyl cyclase–A system functions as a stress-responsive regulator of angiogenesis in mice (2009, The Journal of Clinical Investigation)

Our study revealed that two common symptoms of long COVID, fatigue and brain fog, occur frequently regardless of BNP levels.

In a previous study, we showed an association between ME/CFS and long COVID [22], with approximately 8% of the patients meeting the criteria for ME/CFS. Patients with both ME/CFS and long COVID exhibited symptoms similar to those of patients in the increased BNP group such as fatigue and brain fog.

[22] is Phase-dependent trends in the prevalence of myalgic encephalomyelitis / chronic fatigue syndrome ME/CFS related to long COVID: A criteria-based retrospective study in Japan (2024, PLOS ONE)